EP1915178A1 - Pharmaceutical formulation with high stability and dissolution and manufacturing process - Google Patents
Pharmaceutical formulation with high stability and dissolution and manufacturing processInfo
- Publication number
- EP1915178A1 EP1915178A1 EP06769030A EP06769030A EP1915178A1 EP 1915178 A1 EP1915178 A1 EP 1915178A1 EP 06769030 A EP06769030 A EP 06769030A EP 06769030 A EP06769030 A EP 06769030A EP 1915178 A1 EP1915178 A1 EP 1915178A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical formulation
- weight
- cellulose
- acid
- parts
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 238000004090 dissolution Methods 0.000 title claims abstract description 26
- 238000004519 manufacturing process Methods 0.000 title description 2
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- 239000013543 active substance Substances 0.000 claims abstract description 45
- 239000002904 solvent Substances 0.000 claims abstract description 37
- 239000003463 adsorbent Substances 0.000 claims abstract description 32
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 24
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- 239000002270 dispersing agent Substances 0.000 claims description 10
- 238000002844 melting Methods 0.000 claims description 10
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
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- 230000008018 melting Effects 0.000 claims description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 8
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 4
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- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 4
- 238000000465 moulding Methods 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 claims description 4
- 239000000770 propane-1,2-diol alginate Substances 0.000 claims description 4
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- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
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- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
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- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
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- 239000008389 polyethoxylated castor oil Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000001179 sorption measurement Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 4
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 229940042585 tocopherol acetate Drugs 0.000 description 3
- AHLBNYSZXLDEJQ-UHFFFAOYSA-N N-formyl-L-leucylester Natural products CCCCCCCCCCCC(OC(=O)C(CC(C)C)NC=O)CC1OC(=O)C1CCCCCC AHLBNYSZXLDEJQ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000008206 lipophilic material Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 230000005496 eutectics Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 238000009775 high-speed stirring Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000011858 nanopowder Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000008307 w/o/w-emulsion Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to a pharmaceutical formulation with high stability and dissolution, and a method for preparing the pharmaceutical formulation. More specifically, the present invention relates to a pharmaceutical formulation comprising a pharmacologically active substance, a solvent, a solubilizer, a surfactant, an antioxidant and an adsorbent wherein the pharmacologically active substance is mixed with the solvent, the solubilizer agent and the surfactant for improving the solubility of the pharmacologically active substance to obtain an amorphous liquid or semi-solid state, the antioxidant is melted together with the mixture to solve poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and the adsorbent is strongly adsorbed to the molten mixture so as to be transformed into a powder form so that the resulting molecules are reconstituted into very tiny crystal forms within the adsorbent to ensure chemical stability, the characteristic porous or cellulosic structure of the adsorbent blocks and protects the pharmacologically active
- the solubility of drugs depends on the crystal forms of the drug ingredients.
- the fact is generally known that high crystallinity of drugs leads to poor solubility and low bioavailability of the drugs. Accordingly, disruption of the crystallinity of poorly soluble drugs and transformation of the crystallinity into an amorphous state are of the greatest importance for the improvement of the bioavailability of the drugs.
- [6] 2 a method for preparing an amorphous copolymer by melting a pharmacologically active substance having a low melting point together with a polymer compound having a melting point similar to that of the pharmacologically active substance, and rapidly cooling the molten mixture;
- the crystal forms of some drugs play an important role in stabilizing the drugs.
- the amorphous forms of unstable compounds under general storage conditions may promote denaturation of the unstable compounds.
- orlistat(tetrahydrolipstatin) as a lipase inhibitor or its structurally related compounds are molecules that may be degraded during storage by different mechanisms. It is well known that the degradation rate of active compounds largely depends on the physicochemical states of the active compound.
- the degradation of orlistat is retarded by previously providing a fatty acid ester, which is a degradation product of orlistat, to assist in maintaining the equilibrium of the chemical degradation.
- a fatty acid ester which is a degradation product of orlistat
- the present invention has been made in view of the above problems, and it is an object of the present invention to provide a pharmaceutical formulation that has a crystal form to solve the problems arising from its low melting point and possible degradation under storage conditions, and conversely, can solve the problem of poor solubility resulting from its crystallinity.
- a pharmaceutical formulation comprising a pharmacologically active substance, at least one solvent, at least one solubilizer, at least one surfactant, at least one antioxidant, at least one antioxidative synergist, and an adsorbent wherein the pharmacologically active substance is melted together with the solvent, the solubilizer agent and the surfactant, the antioxidant and the antioxidative synergist are added to ensure chemical stability, the adsorbent is adsorbed to the molten mixture to improve possible chemical instability of the pharmacologically active substance in a liquid state and induce the state of the mixture to a powder form, and the adsorbed mixture is uniformly dispersed so that the active substance is very finely recrystallized within the adsorbent due to a very strong adsorption surface tension.
- the pharmacologically active substance is a substance that is poorly soluble, is unstable under storage conditions, resulting in degradation, and may be rapidly degraded in an amorphous or liquid state.
- the pharmacologically active substance is preferably a lipase inhibitor, and more preferably orlistat (tetrahydrolipstatin) or its analogue, for example, 2-oxy-4H-3,l-benzoxazin-4-one.
- Orlistat is a lipase inhibitor represented by Formula 1 below:
- lipase inhibitor refers to a compound which is capable of inhibiting the action of lipase in the stomach and pancreas.
- Orlistat is a drug having a melting point as low as 43°C, and is commercially available in a powder form.
- the dissolution rate of orlistat undergoing no denaturation under good storage conditions is about 60%. This low dissolution rate of orlistat does not meet the required level of bioavailability.
- the powder particles of orlistat rapidly aggregate. Thereafter, the aggregates remain even when being cooled, causing damage to the dissolution of orlistat. As a result, the dissolution rate of orlistat is sharply reduced to 40% or lower.
- the solubilizer is a pharmaceutically acceptable solvent for the purpose of increasing the bioavailability of the pharmacologically active substance.
- suitable solubilizers include solvents, such as almond oil, castor oil, corn oil, cotton seed oil, ethyl oleate, glycerin, glyceryl monostearate, olive oil, peanut oil, polyethylene glycol, propylene glycol and soy bean oil.
- solubilizers whose one functional group is bonded to the hydrophobic pharmacologically active substance and whose hydrophilic groups are not bonded to the pharmacologically active substance, after which the solubilizers are rapidly dissolved in water through the hydrophilic groups when in contact with water, to solubilize the poorly soluble active substance
- examples thereof include arabic gum, cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, hydroxypropyl cellulose, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid
- the surfactant serves to control the surface tension of lipophilic materials to increase the solubility of the lipophilic materials in water, and is also involved in the dispersion of the liquid-phase pharmacologically active substance.
- the surfactant is preferably provided in an oily state, and is more preferably polysorbate.
- An auxiliary surfactant powder may also be used.
- sodium lauryl sulfate is used.
- the antioxidant plays a fundamental role in preventing the oxidation of the pharmacologically active substance to ensure the storage stability of the drug.
- antioxidants are known to prevent recrystallization and reaggregation of drugs in gastric acid after oral ingestion (see, Korean Patent Application No. 10-2004-0044475).
- examples of such antioxidants are tocopherol, ascorbic acid and its glycosides, butylated hydroxyanisole, citric acid, edetic acid, fumaric acid, malic acid, monoth- ioglycerin, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, and tartaric acid.
- the antioxidant preferably exists in a liquid state at room temperature, and is more preferably tocopherol related materials that are acceptable in pharmaceutical formulations.
- the antioxidative synergist refers to a material that further enhances the an- tioxidizing power of the antioxidant.
- citric acid may be added as an antioxidative synergist.
- two or more antioxidants are used to create synergistic effects. Accordingly, the use of at least one antioxidant and at least one antioxidative synergist is included within the scope of the present invention.
- Dispersants and adsorbents are largely distinguished in terms of their functions.
- adsorbents function to disperse other materials by means of absorbing them, whereas dispersants function to uniformly disperse other materials within a matrix rather than to adsorb the materials.
- the adsorbent used in the present invention has a porous structure, and specifically refers to a material that is present in a colloidal amorphous form or a porous polymeric material.
- adsorbents include: porous mineral materials, such as silicon dioxide, kaolin and magnesium aluminum silicate; polymers that fundamentally adsorb low molecular- weight materials within their structure, such as cyclodextrin and its derivatives, alginic acid and propylene glycol alginate; gums, such as arabic gum and xanthan gum; celluloses, such as cellulose powder, microcrystalline cellulose, ethyl cellulose, methyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hy- droxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; polymers having a major function to disperse other materials, such as poloxamer, povidone and its derivatives, sodium starch glycolate and carbomer.
- porous mineral materials such as silicon dioxide, kaolin and magnesium aluminum silicate
- adsorbents and dispersants are good adsorbents and dispersants.
- These adsorbents may be used alone to perform adsorption/dispersion functions, but mixtures of two or more adsorbents are preferably used to create synergistic effects.
- Preferred is a mixture of a porous colloidal adsorbent and a cellulose type adsorbent.
- a blend with a polymeric adsorbent is very useful.
- Colloidal silicon dioxide and microcrystalline cellulose are more preferably used as adsorbents, and polyvinyl pyrrolidone and sodium starch glycolate are more preferably used as dispersants.
- Crystallinity required in maintaining good chemical stability of orlistat and its related materials is disadvantageous in terms of bioavailability.
- transformation of a crystal form into an amorphous form to increase bioavailability results in damage to chemical stability.
- An important point of the present invention is to provide solutions to satisfy the contradictory requirements.
- the present invention suggests the following solutions: reduction of excessive crystallinity, use of a solubilized composition, improvement of antioxidative ability, use of porous and cellulose type adsorbents to solve instability problems, e.g., hydrolysis, and determination of a pH value suitable to achieve maximum chemical stability.
- a method for preparing the pharmaceutical formulation according to the present invention comprises the steps of:
- solubilization is carried out as rapidly as possible to ensure the stability of the pharmacologically active substance.
- a mixture of the adsorbent and a dispersant powder is fed into a vessel in which high-speed stirring and dispersion can be carried out, and then the previous solution is poured into the vessel with very rapid stirring to induce adsorption and rapid cooling.
- the stirring is carried out at a very high speed for a time sufficient to enable very rapid adsorption and uniform dispersion of the solution.
- the excipient there can be used at least one material selected from Tween 80
- Table 1 shows changes in dissolution rate and content of the tablet samples after six months of storage.
- the pharmaceutical formulation of the present invention overcomes difficulties in the preparation of an active ingredient with a low melting point into a solid formulation, poor solubility of an active ingredient, and danger of chemical modifications during storage.
- a drug can be stably dissolved despite changes in the environments of the body.
- the pharmaceutical formulation of the present invention suitably takes advantage of low melting point and lipophilicity of a drug, it is economically advantageous.
- the pharmaceutical formulation of the present invention has an advantage in that dangers of chemical changes resulting from high energy state of a liquid phase can be reliably avoided.
Abstract
Disclosed herein are a pharmaceutical formulation with high stability and dissolution, and a method for preparing the pharmaceutical formulation. The pharmaceutical formulation comprises a pharmacologically active substance, a solvent, a solubilizer, a surfactant, an antioxidant, and an adsorbent. According to the pharmaceutical formulation and the method, the pharmacologically active substance is mixed with the solvent, the solubilizer agent and the surfactant for improving the solubility of the pharmacologically active substance to obtain an amorphous liquid or semi-solid state, the antioxidant is melted together with the mixture to solve poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and the adsorbent is strongly adsorbed to the molten mixture so as to be transformed into a powder form so that the resulting molecules are reconstituted into very tiny crystal forms within the adsorbent to ensure chemical stability.
Description
Description
PHARMACEUTICAL FORMULATION WITH HIGH STABILITY AND DISSOLUTION AND MANUFACTURING
PROCESS
Technical Field
[1] The present invention relates to a pharmaceutical formulation with high stability and dissolution, and a method for preparing the pharmaceutical formulation. More specifically, the present invention relates to a pharmaceutical formulation comprising a pharmacologically active substance, a solvent, a solubilizer, a surfactant, an antioxidant and an adsorbent wherein the pharmacologically active substance is mixed with the solvent, the solubilizer agent and the surfactant for improving the solubility of the pharmacologically active substance to obtain an amorphous liquid or semi-solid state, the antioxidant is melted together with the mixture to solve poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and the adsorbent is strongly adsorbed to the molten mixture so as to be transformed into a powder form so that the resulting molecules are reconstituted into very tiny crystal forms within the adsorbent to ensure chemical stability, the characteristic porous or cellulosic structure of the adsorbent blocks and protects the pharmacologically active substance from factors, e.g., air and moisture, causing chemical instability of the pharmacologically active substance, and the final pharmaceutical formulation is stabilized within a pH of 4.5 to 5.5.
[2]
Background Art
[3] In most cases, the solubility of drugs depends on the crystal forms of the drug ingredients. The fact is generally known that high crystallinity of drugs leads to poor solubility and low bioavailability of the drugs. Accordingly, disruption of the crystallinity of poorly soluble drugs and transformation of the crystallinity into an amorphous state are of the greatest importance for the improvement of the bioavailability of the drugs.
[4] In this connection, various methods have been known or suggested, for example:
[5] 1) a method for preparing a mixture of a pharmacologically active substance and a dispersant by simultaneously dissolving the pharmacologically active substance and the dispersant in an organic solvent to obtain a mixed solution and injecting the solution at a high speed to rapidly evaporate the organic solvent, thereby preventing the recrystallization of the pharmacologically active substance;
[6] 2) a method for preparing an amorphous copolymer by melting a pharmacologically
active substance having a low melting point together with a polymer compound having a melting point similar to that of the pharmacologically active substance, and rapidly cooling the molten mixture;
[7] 3) a method for preventing recrystallization of a pharmacologically active substance having a low molecular weight by dissolving the pharmacologically active substance in a solvent, and capturing the molecules of the pharmacologically active substance within beta-cyclodextrin cavities;
[8] 4) a method for preparing a liquid formulation or a soft capsule using a mixed solution of a pharmacologically active substance, a solubilizer and a surfactant;
[9] 5) a method for preparing a liquid or powder formulation of a pharmacologically active substance using lecithin liposomes, taking advantage of the physicochemical properties of lecithin to form a hydrophilic and lipophilic sphere layer;
[10] 6) a method for preparing a microemulsion, such as W/O, OAV, 0/W/O a W/O/W emulsion, of a pharmacologically active substance; and
[11] 7) a method for preparing a mixture of a polymer compound and a crystalline pharmacologically active substance at an optimum temperature in a nanopowder form while stirring at a high speed to induce a solid diffusion, as taught in Korean Patent Application No. 10-2004-0044474.
[12] The crystal forms of some drugs, particularly low-melting point drugs, play an important role in stabilizing the drugs. The amorphous forms of unstable compounds under general storage conditions may promote denaturation of the unstable compounds.
[13] Accordingly, pharmaceutical formulations are required to have a crystal form in order to solve the problems arising from their low melting point and possible degradation under storage conditions, and conversely, they must be able to solve the problem of poor solubility resulting from their crystallinity. There is thus a need to develop a pharmaceutical formulation satisfying the requirements.
[14] For example, orlistat(tetrahydrolipstatin) as a lipase inhibitor or its structurally related compounds are molecules that may be degraded during storage by different mechanisms. It is well known that the degradation rate of active compounds largely depends on the physicochemical states of the active compound.
[15] Lipase inhibitors or their structurally related compounds keep their crystal forms to ensure stability during storage, but they accompany solubility difficulties resulting from their crystallinity. Accordingly, both stability and solubility have to be considered in drugs for oral administration. Factors damaging the chemical stability of drugs under general storage conditions are oxidation and reduction reactions. Therefore, it is necessary to design pharmaceutical formulations that are stable against air and moisture. The invention of International Patent Application No. PCT/EP2002/005958
is based on the findings that the eutectic temperature of a mixture of orlistat, a fatty acid or fatty acid salt and water is below body temperature and that a dry powder of the mixture is present in a powder form under storage conditions. According to this invention, the degradation of orlistat is retarded by previously providing a fatty acid ester, which is a degradation product of orlistat, to assist in maintaining the equilibrium of the chemical degradation. However, since the final state of the composition is amorphous as clearly stated in the patent publication, the chemical stability of the composition is incompletely ensured, the preparation involves complicated steps, and the stability is not continuously guaranteed.
[16] International Patent Application No. PCT/EP2001/06834 describes a porous formulation which is expanded in solutions and dispersions. However, the disadvantage of the formulation is that the preparation procedure is very complicated.
[17]
Disclosure of Invention Technical Problem
[18] Therefore, the present invention has been made in view of the above problems, and it is an object of the present invention to provide a pharmaceutical formulation that has a crystal form to solve the problems arising from its low melting point and possible degradation under storage conditions, and conversely, can solve the problem of poor solubility resulting from its crystallinity.
[19]
Technical Solution
[20] In accordance with an aspect of the present invention for achieving the above object, there is provided a pharmaceutical formulation comprising a pharmacologically active substance, at least one solvent, at least one solubilizer, at least one surfactant, at least one antioxidant, at least one antioxidative synergist, and an adsorbent wherein the pharmacologically active substance is melted together with the solvent, the solubilizer agent and the surfactant, the antioxidant and the antioxidative synergist are added to ensure chemical stability, the adsorbent is adsorbed to the molten mixture to improve possible chemical instability of the pharmacologically active substance in a liquid state and induce the state of the mixture to a powder form, and the adsorbed mixture is uniformly dispersed so that the active substance is very finely recrystallized within the adsorbent due to a very strong adsorption surface tension.
[21]
Best Mode for Carrying Out the Invention
[22] The pharmacologically active substance is a substance that is poorly soluble, is unstable under storage conditions, resulting in degradation, and may be rapidly
degraded in an amorphous or liquid state. The pharmacologically active substance is preferably a lipase inhibitor, and more preferably orlistat (tetrahydrolipstatin) or its analogue, for example, 2-oxy-4H-3,l-benzoxazin-4-one.
[23] Orlistat is a lipase inhibitor represented by Formula 1 below:
[24]
(D
[25] The term "lipase inhibitor" refers to a compound which is capable of inhibiting the action of lipase in the stomach and pancreas.
[26] Orlistat is a drug having a melting point as low as 43°C, and is commercially available in a powder form. The dissolution rate of orlistat undergoing no denaturation under good storage conditions is about 60%. This low dissolution rate of orlistat does not meet the required level of bioavailability. In addition, when raw materials of orlistat are exposed to high temperature during transport, the powder particles of orlistat rapidly aggregate. Thereafter, the aggregates remain even when being cooled, causing damage to the dissolution of orlistat. As a result, the dissolution rate of orlistat is sharply reduced to 40% or lower.
[27] The solubilizer is a pharmaceutically acceptable solvent for the purpose of increasing the bioavailability of the pharmacologically active substance. Examples of suitable solubilizers include solvents, such as almond oil, castor oil, corn oil, cotton seed oil, ethyl oleate, glycerin, glyceryl monostearate, olive oil, peanut oil, polyethylene glycol, propylene glycol and soy bean oil. Included also are solubilizers whose one functional group is bonded to the hydrophobic pharmacologically active substance and whose hydrophilic groups are not bonded to the pharmacologically active substance, after which the solubilizers are rapidly dissolved in water through the hydrophilic groups when in contact with water, to solubilize the poorly soluble active substance, and examples thereof include arabic gum, cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, hydroxypropyl cellulose, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, and triethanolmine. These solubilizers may be used alone or as a
mixture thereof. The solubilizers are preferably present in a liquid state at room temperature. More preferred are polyethylene glycol and polyoxyethylene castor oil glycoside.
[28] The surfactant serves to control the surface tension of lipophilic materials to increase the solubility of the lipophilic materials in water, and is also involved in the dispersion of the liquid-phase pharmacologically active substance. Exemplary surfactants include sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (polysorbate= Tween), sodium lauryl sulfate, sorbic acid, and sorbitan fatty acid ester. The surfactant is preferably provided in an oily state, and is more preferably polysorbate. An auxiliary surfactant powder may also be used. As a preferred auxiliary surfactant, sodium lauryl sulfate is used.
[29] The antioxidant plays a fundamental role in preventing the oxidation of the pharmacologically active substance to ensure the storage stability of the drug. In addition, antioxidants are known to prevent recrystallization and reaggregation of drugs in gastric acid after oral ingestion (see, Korean Patent Application No. 10-2004-0044475). Examples of such antioxidants are tocopherol, ascorbic acid and its glycosides, butylated hydroxyanisole, citric acid, edetic acid, fumaric acid, malic acid, monoth- ioglycerin, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, and tartaric acid. The antioxidant preferably exists in a liquid state at room temperature, and is more preferably tocopherol related materials that are acceptable in pharmaceutical formulations.
[30] The antioxidative synergist refers to a material that further enhances the an- tioxidizing power of the antioxidant. For example, when tocopherol is used as an antioxidant, citric acid may be added as an antioxidative synergist. In most cases, two or more antioxidants are used to create synergistic effects. Accordingly, the use of at least one antioxidant and at least one antioxidative synergist is included within the scope of the present invention.
[31] Dispersants and adsorbents are largely distinguished in terms of their functions.
That is, adsorbents function to disperse other materials by means of absorbing them, whereas dispersants function to uniformly disperse other materials within a matrix rather than to adsorb the materials. The adsorbent used in the present invention has a porous structure, and specifically refers to a material that is present in a colloidal amorphous form or a porous polymeric material. Examples of such adsorbents include: porous mineral materials, such as silicon dioxide, kaolin and magnesium aluminum silicate; polymers that fundamentally adsorb low molecular- weight materials within their structure, such as cyclodextrin and its derivatives, alginic acid and propylene glycol alginate; gums, such as arabic gum and xanthan gum; celluloses, such as cellulose powder, microcrystalline cellulose, ethyl cellulose, methyl cellulose, calcium
carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hy- droxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose; polymers having a major function to disperse other materials, such as poloxamer, povidone and its derivatives, sodium starch glycolate and carbomer. In addition to these dispersants, dextrin, gelatin, medium-chain triglyceride, tragacanth, and the like, are good adsorbents and dispersants. These adsorbents may be used alone to perform adsorption/dispersion functions, but mixtures of two or more adsorbents are preferably used to create synergistic effects. Preferred is a mixture of a porous colloidal adsorbent and a cellulose type adsorbent. Further, a blend with a polymeric adsorbent is very useful. Colloidal silicon dioxide and microcrystalline cellulose are more preferably used as adsorbents, and polyvinyl pyrrolidone and sodium starch glycolate are more preferably used as dispersants.
[32] Crystallinity required in maintaining good chemical stability of orlistat and its related materials is disadvantageous in terms of bioavailability. However, transformation of a crystal form into an amorphous form to increase bioavailability results in damage to chemical stability. An important point of the present invention is to provide solutions to satisfy the contradictory requirements. To this end, the present invention suggests the following solutions: reduction of excessive crystallinity, use of a solubilized composition, improvement of antioxidative ability, use of porous and cellulose type adsorbents to solve instability problems, e.g., hydrolysis, and determination of a pH value suitable to achieve maximum chemical stability.
[33] A method for preparing the pharmaceutical formulation according to the present invention comprises the steps of:
[34] mixing 0.01-20 parts by weight of the solvent, 0.01-20 parts by weight of the solubilizer, 0.01-10 parts by weight of the surfactant and 0.01-2 parts by weight of the antioxidant with heating to 40-600C;
[35] mixing the mixture with 1 part by weight of the pharmacologically active substance;
[36] adsorbing the mixture obtained in the previous step to 0.1-20 parts by weight of the adsorbent;
[37] mixing the mixture obtained in the previous step with a pharmaceutically acceptable excipient suitable for molding; and
[38] molding the mixture obtained in the previous step into a tablet followed by coating or capsule.
[39] In the step of mixing with the pharmacologically active substance, solubilization is carried out as rapidly as possible to ensure the stability of the pharmacologically active substance. In the step of adsorbing to the adsorbent, a mixture of the adsorbent and a dispersant powder is fed into a vessel in which high-speed stirring and dispersion can
be carried out, and then the previous solution is poured into the vessel with very rapid stirring to induce adsorption and rapid cooling. At this step, the stirring is carried out at a very high speed for a time sufficient to enable very rapid adsorption and uniform dispersion of the solution.
[40] As the excipient, there can be used at least one material selected from Tween 80
(polysorbate 80), PVP K-30 (polyvinylpyrrolidone), and talc (Mg (OH) Si O ).
3 2 4 10
[41]
Mode for the Invention
[42] Hereinafter, the pharmaceutical formulation of the present invention will be explained in more detail with reference to the following examples.
[43] EXAMPLES
[44] Example 1:
[45] 1Og of polyethylene glycol 400, 1Og of polyoxyethylene castor oil (Cremophor),
1Og of polysorbate and 5g of tocopherol acetate were heated to 40-600C, and then 12Og of orlistat was added thereto. The mixture was homogeneously stirred to prepare a pale yellow transparent liquid formulation. The liquid state was transformed into an opaque coagulated state at room temperature.
[46] Some portions were used to conduct a test for liquid stability. The other portions were adsorbed to an adsorbent, and then an excipient was added thereto. The resulting mixture was pressed to produce tablets, followed by coating with a film to obtain 800 tablet samples.
[47] 1) The liquid samples were cooled to form a coagulated material. The coagulated material had uniform shape and composition, and showed no phase separation and reaggregation. A series of storage at a low temperature of 4°C and storage at a high temperature of 400C was repeated several times, and thereafter, a dissolution test was conducted. As a result, a high dissolution rate of 99.1% was obtained.
[48] However, degradation of the liquid was observed after six weeks of storage under accelerated storage conditions. In addition, a 15% reduction in content was observed. Dark particles as degradation products and layers in which the dark particles were dispersed were observed.
[49] 2) The tablet samples were stored under accelerated conditions (temperature: 400C, relative humidity: 70%).
[50] Table 1 shows changes in dissolution rate and content of the tablet samples after six months of storage.
[51] Table 1
Change in content Change in dissolution rate
[52]
[53] Example 2:
[54] 1Og of polyoxyethylene castor oil (Cremophor) was heated to 40-600C to obtain a transparent liquid, and then 1Og of polysorbate was added thereto with gentle stirring. 12Og of orlistat was added to the mixture and homogeneously stirred to form a pale yellow transparent liquid formulation. The liquid state was transformed into an opaque coagulated state at room temperature.
[55] Some portions were taken to observe the state of the liquid, and the other portions were adsorbed to produce tablets, followed by coating to obtain 800 tablet samples.
[56] 1) No phase separation and reaggregation were observed in the liquid samples. By the procedure of Example 1, a series of storage at a low temperature and storage at a high temperature was repeated several times, and thereafter, a dissolution test was conducted. As a result, a dissolution rate of about 59% was obtained. These observations indirectly show that the selected solvent in the present invention was suitable and inevitable to maximize the efficiency of the solubilizer, surfactant and antioxidant. After 2 weeks of storage under accelerated conditions, degradation products and layers thereof were observed.
[57] 2) The dissolution of the tablet samples was tested, and as a result, satisfactory results were not attained.
[58]
[59] Example 3:
[60] When 1Og of polyethylene glycol, 1Og of polysorbate and 5g of tocopherol acetate were mixed with heating to obtain a transparent liquid, 12Og of orlistat was added to the mixture. The resulting mixture was homogeneously stirred to prepare a pale yellow transparent liquid formulation. The liquid state was transformed into an opaque semi- coagulated state at room temperature.
[61] By the procedure of Example 1, some portions were separated, rapidly adsorbed, and pressed to produce tablets.
[62] 1) Phase separation, reaggregation and recrystallization of the separated liquid samples were observed during coagulation. By the procedure of Example 1, a series of storage at a low temperature and storage at a high temperature was repeated several times, and thereafter, a dissolution test was conducted. As a result, a dissolution rate of about 23% was obtained. These observations demonstrate that the solubilizer is an inevitable ingredient for stable dissolution of the formulation. After 2 weeks of storage under accelerated conditions, degradation products and layers thereof were observed.
[63] 2) The dissolution rate of the tablet samples was tested, and as a result, dissolution rates of the table samples were not significantly different from those of the liquid samples.
[64]
[65] Example 4:
[66] 1Og of polyethylene glycol, 1Og of polyoxyethylene castor oil (Cremophor) and 5g of tocopherol acetate were mixed and homogeneously stirred with heating to prepare a transparent solution, and then 12Og of orlistat was added to the solution. The mixture was homogeneously stirred to prepare a pale yellow transparent liquid formulation.
[67] 1) The liquid state was transformed into an opaque semi-coagulated state at room temperature. No phase separation and reaggregation were observed. A series of storage at a low temperature and storage at a high temperature was repeated several times, and thereafter, a dissolution test was conducted. As a result, a dissolution rate of 88% was obtained. However, a reduction in content was observed after four weeks of storage under accelerated storage conditions. Degradation products and layers thereof were observed.
[68] 2) An adsorbed powder was pressed to produce tablets, followed by coating to obtain tablet samples. The tablet samples were stored under accelerated conditions for 6 months. Table 2 shows changes in dissolution rate and content of the tablet samples during storage.
[69] Table 2
[70] The data shown in Table 2 demonstrate that the surfactant contributed significantly to dissolution of the pharmacologically active substance. [71]
[72] Example 5:
[73] 1Og of polyethylene glycol and 1Og of polyoxyethylene castor oil (Cremophor) were mixed and homogeneously stirred with heating to prepare a transparent solution, and then 12Og of orlistat was added to the solution. The mixture was homogeneously stirred to prepare a pale yellow transparent liquid formulation. [74] 1) The liquid state was transformed into an opaque coagulated state at room temperature. No phase separation, recrystallization and reaggregation were observed.
These observations demonstrate that the antioxidant was involved in recrystallization and reaggregation to prevent occurrence of phase separation during aggregation. A
series of storage at a low temperature and storage at a high temperature was repeated several times, and thereafter, a dissolution test was conducted. As a result, a high dissolution rate of 95% was obtained. This suggests that phase separation and reag- gregation during coagulation do not lead to a reduction in dissolution rate, and an optimum blending of the solvent, the solubilizer and the surfactant leads to effective dissolution. However, a reduction in the liquid content was observed after four weeks of storage under accelerated storage conditions. Degradation products and layers thereof were also observed.
[75] 2) An adsorbed powder was pressed to produce tablets, followed by coating to obtain coated tablet samples. The tablet samples were stored under accelerated conditions for 6 months. Table 3 shows changes in dissolution rate and content of the tablet samples during storage.
[76] [77] Table 3
[78] As can be seen from the data shown in Table 3, tocopherol was significantly involved in the stability of the drug (i.e. orlistat). [79] Table 4 shows contents of the ingredients in each of the tablets produced in Examples 1 to 5.
[80] [81] Table 4
[82] Surprisingly the present inventors have found that when a pharmacologically active substance is mixed with a solvent, a solubilizer agent and a surfactant for improving the solubility of the pharmacologically active substance to obtain an amorphous liquid or semi-solid state, an antioxidant is melted together with the mixture to solve poor chemical stability of the pharmacologically active substance in an amorphous or liquid state, and an adsorbent is strongly adsorbed to the molten mixture so as to be transformed into a powder form, the resulting very small molecules are reconstituted into crystal forms within the adsorbent to ensure chemical stability, the characteristic porous or cellulosic structure of the adsorbent blocks and protects the pharmacologically active substance from factors, e.g., air and moisture, causing chemical instability of the pharmacologically active substance, and the final pharmaceutical formulation is stabilized within a pH (as measured using an aqueous solution of Ig of the pharmaceutical formulation in 100 ml of water) of 4.5 to 5.5. The present invention has been achieved based on these findings.
[83]
Industrial Applicability [84] As apparent from the above description, the pharmaceutical formulation of the present invention overcomes difficulties in the preparation of an active ingredient with a low melting point into a solid formulation, poor solubility of an active ingredient, and danger of chemical modifications during storage. In addition, according to the pharmaceutical formulation of the present invention, a drug can be stably dissolved despite changes in the environments of the body. Furthermore, since the pharmaceutical formulation of the present invention suitably takes advantage of low melting point and lipophilicity of a drug, it is economically advantageous. Moreover, the pharmaceutical formulation of the present invention has an advantage in that dangers of chemical changes resulting from high energy state of a liquid phase can be reliably avoided. [85] Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope
and spirit of the invention as disclosed in the accompanying claims.
Claims
[1] A pharmaceutical formulation with high stability and dissolution, the pharmaceutical formulation comprising 1 part by weight of orlistat, a lipase inhibitor, or its analogue as a pharmacologically active substance that is poorly soluble and has a low melting point, 0.01 to 20 parts by weight of a solvent, 0.01 to 20 parts by weight of a solubilizer, 0.01 to 10 parts by weight of a surfactant, 0.01 to 2 parts by weight of an antioxidant, and 0.1 to 20 parts by weight of an adsorbent or dispersant.
[2] The pharmaceutical formulation according to claim 1, wherein the solvent is selected from almond oil, castor oil, corn oil, cotton seed oil, ethyl oleate, glycerin, glyceryl monostearate, olive oil, peanut oil, polyethylene glycol, propylene glycol, soy bean oil, and mixtures thereof.
[3] The pharmaceutical formulation according to claim 1, wherein the solubilizer is selected from arabic gum, cetostearyl alcohol, cholesterol, diethanolamine, ethyl oleate, ethylene glycol palmitostearate, glycerin, glyceryl monostearate, hy- droxypropyl cellulose, isopropyl myristate, lecithin, medium-chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl ether, polyoxyethylene castor oil glycoside, polyethylene sorbitan fatty acid ester, polyoxyethylene stearate, propylene glycol alginate, sorbitan fatty acid ester, stearic acid, sunflower oil, triethanolmine, and mixtures thereof.
[4] The pharmaceutical formulation according to claim 1, wherein the surfactant is selected from sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (poly sorbate=T ween), sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof.
[5] The pharmaceutical formulation according to claim 1, wherein the antioxidant is selected from tocopherol, ascorbic acid and its glycosides, butylated hy- droxyanisole, citric acid, edetic acid, fumaric acid, malic acid, monothioglycerin, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, tar acid, and mixtures thereof.
[6] The pharmaceutical formulation according to claim 1, wherein the adsorbent or dispersant is selected from silicon dioxide, kaolin, magnesium aluminum silicate, cyclodextrin and its derivatives, alginic acid, propylene glycol alginate, gums, including arabic gum and xanthan gum, celluloses, including cellulose powder, microcrystalline cellulose, ethyl cellulose, methyl cellulose, calcium car- boxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose and hydroxypropylmethyl cellulose, poloxamer, povidone and its derivatives, sodium starch glycolate,
carbomer, dextrin, gelatin, medium-chain triglyceride, tragacanth, and mixtures thereof.
[7] The pharmaceutical formulation according to claim 1, wherein the pharmaceutical formulation has a pH of 4.5 to 5.5.
[8] A method for preparing a pharmaceutical formulation with high stability and dissolution, the method comprising the steps of: mixing 0.01-20 parts by weight of a solvent, 0.01-20 parts by weight of a solubilizer, 0.01-10 parts by weight of a surfactant and 0.01-2 parts by weight of an antioxidant with heating to 40-60°C(step Sl); mixing the mixture obtained in step Sl with 1 part by weight of a pharmacologically active substance (step S2); adsorbing the mixture obtained in step S2 to 0.1-20 parts by weight of an adsorbent (step S3); mixing the mixture obtained in step S3 with a pharmaceutically acceptable excipient suitable for molding (step S4); and molding the mixture obtained in step S4 into a tablet followed by coating or capsule(step S5)
Applications Claiming Priority (2)
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KR1020050075266A KR100669497B1 (en) | 2005-08-17 | 2005-08-17 | Pharmaceutical formulation with high stability and dissolution and manufacturing method |
PCT/KR2006/002452 WO2007021073A1 (en) | 2005-08-17 | 2006-06-26 | Pharmaceutical formulation with high stability and dissolution and manufacturing process |
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US (1) | US20080200536A1 (en) |
EP (1) | EP1915178A4 (en) |
JP (1) | JP2009504728A (en) |
KR (1) | KR100669497B1 (en) |
CN (1) | CN101237891B (en) |
AU (1) | AU2006280615A1 (en) |
BR (1) | BRPI0615553A2 (en) |
CA (1) | CA2617140C (en) |
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KR101252635B1 (en) | 2006-04-20 | 2013-04-10 | (주)아모레퍼시픽 | Pharmaceutical composition comprising a lipase inhibitor and a lipophilic oil absorbant and oral formulation prepared therefrom |
PL2002825T3 (en) * | 2007-06-14 | 2013-12-31 | Krka | Pharmaceutical compositions comprising orlistat |
WO2009044380A2 (en) | 2007-10-05 | 2009-04-09 | Ranbaxy Laboratories Limited | Formulations containing orlistat particles having controlled particle size |
KR100958892B1 (en) * | 2007-12-27 | 2010-05-20 | 한미약품 주식회사 | Preconcentrate comprising a stool softner and a surfactant |
WO2012082083A1 (en) * | 2010-12-15 | 2012-06-21 | Les Laboratoires Medis Sa | Pharmaceutical formulation containing tetrahydrolipstatin as an active ingredient |
CN102362863B (en) * | 2011-11-21 | 2013-06-12 | 山东新时代药业有限公司 | Orlistat-containing preparation and preparation method thereof |
JP2013147488A (en) * | 2011-12-21 | 2013-08-01 | Taisho Pharmaceutical Co Ltd | Solid preparation |
CN102552168B (en) * | 2012-01-31 | 2013-08-07 | 杭州华东医药集团生物工程研究所有限公司 | Pharmaceutical composition containing orlistat and its preparation method |
JP6075043B2 (en) * | 2012-12-05 | 2017-02-08 | 大正製薬株式会社 | Solid preparation |
KR20140112747A (en) * | 2013-03-14 | 2014-09-24 | 연세대학교 산학협력단 | Pharmaceutical composition for enhancing elution of lipase inhibitor and reducing side effects and the preparation thereof |
CN106349192B (en) * | 2016-10-10 | 2018-06-22 | 中山万汉制药有限公司 | The eutectic of orlistat and amino acid and include eutectiferous pharmaceutical composition |
CN107412176A (en) * | 2017-05-21 | 2017-12-01 | 天津双硕医药科技有限公司 | A kind of fat-reducing tablet containing orlistat |
JP7166754B2 (en) | 2017-11-22 | 2022-11-08 | 沢井製薬株式会社 | Formulations containing dasatinib anhydrate |
CN110013467B (en) | 2018-01-10 | 2021-09-17 | 上海汉都医药科技有限公司 | Solid particle, preparation method thereof and pharmaceutical composition containing solid particle |
CN108440456B (en) * | 2018-03-22 | 2020-01-03 | 中山万汉制药有限公司 | Co-crystal of orlistat and organic acid calcium and pharmaceutical composition containing co-crystal |
CN109157523B (en) * | 2018-10-09 | 2020-07-28 | 中山万汉制药有限公司 | Orlistat dripping pill and its prepn |
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US6635281B2 (en) * | 1998-12-23 | 2003-10-21 | Alza Corporation | Gastric retaining oral liquid dosage form |
US6333029B1 (en) * | 1999-06-30 | 2001-12-25 | Ethicon, Inc. | Porous tissue scaffoldings for the repair of regeneration of tissue |
AR025587A1 (en) * | 1999-09-13 | 2002-12-04 | Hoffmann La Roche | DISPERSION FORMULATIONS CONTAINING LIPASA INHIBITORS |
AR025609A1 (en) * | 1999-09-13 | 2002-12-04 | Hoffmann La Roche | SOLID LIPID FORMULATIONS |
US20020016307A1 (en) * | 1999-10-27 | 2002-02-07 | Mullins John Jason Gentry | Pharmaceutical composition with both a lipase inhibitor and a lipophilic polysaccharide and an improved method for treating adiposity |
SI1296656T1 (en) * | 2000-06-27 | 2006-12-31 | Hoffmann La Roche | Method for preparing a composition |
US6730319B2 (en) * | 2001-06-06 | 2004-05-04 | Hoffmann-La Roche Inc. | Pharmaceutical compositions having depressed melting points |
EP1470116A4 (en) * | 2001-12-04 | 2005-04-06 | Biogal Gyogyszergyar | Preparation of orlistat and orlistat crystalline forms |
WO2004096202A1 (en) * | 2003-04-28 | 2004-11-11 | Cipla Limited | Pharmaceutical formulation comprising anti-obesity agent and acidulant |
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BRPI0615553A2 (en) | 2011-05-24 |
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CN101237891A (en) | 2008-08-06 |
US20080200536A1 (en) | 2008-08-21 |
CN101237891B (en) | 2011-06-08 |
WO2007021073A1 (en) | 2007-02-22 |
EP1915178A4 (en) | 2010-01-13 |
CA2617140A1 (en) | 2007-02-22 |
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